Precision and sensitivity of pharmacokinetic models for cancer risk assessment: tetrachloroethylene in mice, rats, and humans.
Pharmacokinetic analyses have recently been incorporated in risk assessments, with resultant risks sometimes lower and associated "allowable" exposures higher, than would have been otherwise calculated. Predictions of coupled pharmacokinetic and multistage models, as used for regulatory purposes, are evaluated here for tetrachloroethylene carcinogenicity in mice, rats, and humans. Precision is studied by treating parameters as random variables and determining the range of risk estimates once parameter uncertainties are considered via Monte Carlo simulations. The methods developed in this study are of interest for any similar application. The resultant median risk estimate for humans exposed continuously to 1 ng/liter of tetrachloroethylene in the air is 1.6 per million and 5, 25, 75, and 95 percentiles are 0, 0.04, 2.8, and 6.8 per million. Sensitivity of the pharmacokinetic model predictions to its parameters is assessed by analyzing the results of the Monte Carlo simulations. The kinetic parameters defining the metabolic rate are the most important for the case studied.
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Department of Pharmacy, University of California, San Francisco 94143-0446.
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D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D012306:Risk; D013750:Tetrachloroethylene / Q000493:pharmacokinetics* / Q000633:toxicity
D013750:Tetrachloroethylene